Genes newly associated with body weight

Research UpdateDec. 22, 2017

Scientists’ recent analysis of hundreds of thousands of human genomes has identified new links between certain gene sequence variations and body mass index (BMI), a measure of weight relative to height. Obesity is a complex condition that can be caused by multiple factors, including a person’s genes. Identifying the genes (and the specific natural variations in those genes) that contribute to body weight regulation can provide new information on what causes obesity and how best to treat it. Genome-wide association studies (GWAS) have been used to rapidly scan the DNA of large groups of study participants, with the aim of finding genetic variations linked to differences in BMI. Previously, analysis of common variations identified though GWAS have led to identification of some of the mechanisms involved in regulating body weight. It has been challenging, though, to identify what specific genetic variants govern this regulation, as identified variants were sometimes outside the “exome”—regions of the genome that code for proteins—making it unclear how those variants affect cell function. Further, most GWAS to date have identified fairly common variations, and less common variations may also shed light on the biology of obesity. To identify more BMI-specific genes and gene variants, researchers scanned only the exomes of over 700,000 individuals who participated in 125 clinical studies, looking for uncommon or rare gene variants that correlated with higher or lower BMI. The study identified 14 uncommon gene variants in 13 genes, with one of the variants only being associated with BMI in females. Eight of these genes had never before been implicated in human obesity. Further investigation of these variants showed that the four that were least common affected BMI on average about 10 times more strongly than more common, previously identified obesity-related variants. Researchers found that many of these newly BMI-associated rare gene variants coded for proteins that are enriched in the brain, and further research is needed to fully understand their role in body weight. None of the identified variants contributed significantly to BMI variation in the overall population, but they may substantially affect the weight of individual people. Overall, these findings provide new insight into the causes of obesity, which could lead to new therapeutic targets and more personalized obesity treatments.